GB2244055A - Resolution of glycidic acid derivatives - Google Patents

Abstract

The kinetic resolution of a mixture of cis or trans enantiomers of a compound of the formula <IMAGE> (R3 = C1-18-alkoxy, benzyloxy, NH2, NH-C1-6-alkyl or N-(C1-6-alkyl)2; X = CH3O, OH or protected OH (e.g. an ester or bentyl ether thereof); and the asterisks mark the asymmetric carbon atoms) is effected by reaction with a thiophenol of formula <IMAGE> (R4, R5 = H,Cl,C1-4-alkyl, NH2, NHCOCH3, NO2) in the presence of a catalytic amount of an optically active tertiary amine in an inert solvent at -20 to +30 DEG C. A product of formula <IMAGE> is obtained together with unreacted epoxide (III-A), each substance having a high enantiomerich purity. The resolution is useful in the synthesis of Diltiazem and related cardiovascular drugs.

Description

TITLE Resolution of glycidic acid derivatives

DESCRIPTION

The invention relates to a process for the resolution of glycidic acid derivatives and, more particularly, it relates to a process for the resolution of 3- (4 -subs tituted-phenyl) -glycidic acid derivatives such as esters and amides.

Ester and amide derivatives of 3-(4methoxy-phenyl)-glycidic acid are intermediates for the synthesis of compounds active on the cardiovascular system such as optically active 2,3-dihydro-2-(4methoxyphenyl)-1, 5-benzothiazepin-4(5H)-ones of formula OCH3 C0 S R, OR (I)-cis N 1 CH:m CH2-CH2-N CH:3 wherein R represents a hydrogen atom or an acetyl group; R 1 represents a hydrogen or chlorine atom; and the asterisks mark the asymmetric carbon atoms.

Specific examples of the compounds of formula I are Diltiazem,(+)-(2S,3S)3-acetoxy-5-[2-(dimethylamino)-ethyll-2,3-dihydro-2-(4-methoxyphenyl-1,5benzothiazepin-4(5H)-one (Merck Index, X Ed., No. 3189, page 466) and TA-3090, (+)-(2S,3S)-3-acetoxy-8-chloro-512- 2 -(dimethylamino)-ethyll-2,3-dihydro-2-)4-methoxyphenyl) -1, 5benzothiazepin-4(5H) -one (Annual Drug Data Report 1987, page 507).

1 Various methods for the preparation of the compounds of formula 1 are known. Amongst these are those described in British Patent No. 1236467 European Patents Nos.

127882 and 158340 and British Patent Application No.

2167063, all in the name of Tanabe Seiyaku Co. Ltd.

Most of these methods substantially foresee the following reaction scheme.

SH R, 1 Oi 0 CH30 0 CH-CH-COOR2)y II W OCH, 0 III-trans Ri- 0 / ---=- OH \NH2 COOR2 IV-threo V1 OCH3 S Ri- 0 OH NH2 COOH V-threo W 0 S - - OH - 0 0 - OH N - H 0 OCH3 VI-Cis I wherein R 1 represents a hydrogen or chlorine atom; R2 represents a lower alkyl group and the asterisks mark the asymmetric carbon atoms.

A similar synthesis in which a 2-nitro-thiophenol is used instead of Compound II and the nitro group of the condensation product is reduced to an amino group before the cyclization reaction has also been described (European Patent No. 59335 - Tanabe Seiyaku Co. Ltd.).

Each of these methods necessarily foresees an optical resolution step, generally at the level of an intermediate of the synthesis, in order to separate the enantiomer with the desired configuration. Resolution of the cyclic intermediate of formula VI by 1-(2-naphthylsulphonyl)-pyrrolidine-2-carbonyl chloride is described in British Patent Application No. 2167063. Resolution of the intermediate of formula V by optically active bases is also known. European Patent No. 127882 describes such a resolution using 4- hydroxyphenyl-glycine methyl ester or cinchonidine; European Patent No. 98892 (Tanabe Seiyaku Co. Ltd.) describes such a resolution using a- phenethylamine; British Patent No. 2130578 (Istituto Luso Farmaco) describes such a resolution using L-lysine.

Resolution at an earlier step of the synthesis, that is at the level of glycidic intermediate III, would be of interest. Recently, an enzymatic resolution of esters of formula III (R 2 =1'ower alkyl) has been described (European Patent Application No. 343714 - Stamicarbon B.V.). However, enzymatic resolutions are seldom economically more advantageous than chemical resolutions because the enzyme, which may have a high cost, must be recovered and it loses its specific activity in time. Chemical resolutions have been described at the level of free acid III (R 2 =H) by using an optically active base which affords diastereoisomeric salts. However, in this specific case, such a resolution is particularly laborious and difficult because of the instability of free acid III (R 2 =H).

Wehave found a kinetic resolution process which allows the compounds of formula III or their precursors to be obtained with a high enantiomeric purity starting from mixtures of cis enantiomers (2S, 3S and 2R, 3R) or of trans enantiomers (2R, 3S and 2S, 3R) In particular, the invention provides a process for the kinetic resolution of a mixture of cis or trans enantiomers of a compound of formula 0 X 0 /\ CH-CH-CO-R3 (III-A) wherein R 3 represents a linear or branched Cl- C 18 alkoxy group, a benzyloxy otamino group, or a mono or dialkylamino group in which the or each alkyl moiety has from 1 to 6 carbon atoms; X represents a methoxy group or a group transformable into a methoxy group, said transformable group being a free hydroxy group or a hydroxy group protected as benzyloxy or as an ester with an acid usually used for protecting phenols; and the asterisks mark the asymmetric carbon atoms; the process comprising reacting a racemic mixture of cis or trans enantiomers of the compounds of formula III-A witha thiophenol of formula R., A r Rs SH (II-A) wherein each of R 4 and R 5 independently represents a hydrogen or chlorine atom, or a C 1- C 4 alkyl, amino, acetylamino or nitro group-, in the presence of a catalytic amount of an optically active tertiary amine in an inert solvent at a temperature of from -20C to +30C.

The above process consists in a kinetic resolution since, under the above reported conditions, one of the two enantiomers reacts with thiophenol IIA faster than the other in order to give a compound of formula 1 / X j sR,- 0 OH COR3 Res M-M wherein R 3' R 41 R 5 and X have the above defined meanings; this is a result of a trans-type opening of the epoxy ring. By quenching the reaction at about 50% conversion, the other enantiomer remains in solution in an unreacted form witha high enantiomeric purity.

The nature of the optically active tertiary amine determines which of the two enantiomers reacts faster. Although the reaction mechanism has not yet been explained, our experimental observations suggest that the reaction proceeds through an attack of an ammonium thiophenate (obtained in situ by reaction of thiophenol II-A with the optically active tertiary amine) on the epoxy ring of compound III-A with trans opening of the ring. Since the first reaction in scheme 1 can be carried out through a cis opening (in basic environment) as well as through a trans opening (thermic) of the epoxide, it is clear that the present process is particularly advantageous because, in addition to the good results of the kinetic resolution, it allows the use of compounds III-A with cis configuration for the synthesis of the compounds of formula I.

Asreported above,the selection of the optically active tertiary amine determines which of the two enantiomers of compound III-A reacts faster. For example, starting from a mixture of trans enantiomers III-A (2R,3S and 2S, 3R) it is possible to carry out the reaction on the (2S,3R) enantiomer preferentially while keeping unchanged the (2R,3S) enantiomer which, by thermic condensation with 2-amino-thiophenol, directly gives the compound IV of scheme 1 in the right configuration.

Analogously, starting from racemic cis-compound III-A, the kinetic resolution gives (2R,3R) enantiomer III-A which, by subsequent reaction with 2 -amino- thi ophenol in a basic environment, gives the intermediate IV of scheme 1 in the right configuration. On the contrary, if the process of the invention is carried out under conditions in which the reaction is faster on (2R,3R) enantiomer III-A, the use of 2-aminothiophenol as compound of formula II-A directly gives the compound IV of scheme 1 in the right configuration.

It is clear that the process of the invention is equally applicable to the scheme 1 synthesis variant described in European Patent No. 59335.

The critical factors and the parameters of the process of the invention are now discussed.

substrate: (compounds of formula III-A) As above reported, the process may be carried out on racemic mixtures of cis as well as trans enantiomers III-A. The two substrates (cis or trans mixtures) are equivalent and this is an advantage since it allows cis enantiomers III-A to be used in the synthesis of the compounds of formula 1. As far as the substituents of the compounds of formula III-A are concerned, the usefulness of having the carboxy group in the form of an ester with alcohols having a low as well as a high number of carbon atoms or in the form of an amide lies in the consequent possibility of modulating the lipophilicity of compound III-A as a function of the other reaction parameters. Substituent X can also be selected dependent upon several factors such as the possibility of modulating the lipophilicity of compound III-A. For this purpose, a suitably protected hydroxy group can be used.

For a comprehensive reference to the protection of phenols and their deprotection see Theodora W. Greene Protective Groups in Organic Synthesis - Chapter 3, pages 87-108 - John Wiley & Sons.

obviously, the preferred substituent X is methoxy because it is the substituent present in the compounds of formula 1. Reagent Specific examples of the thiophenols of formula II-A are thiophenol, 4-methyl-thiophenol, 4-isopropyl- -thiophenol, 4-tert.butyl-thiophenol, 2-amino-thiophenol, 2-nitro-thiophenol, 2-amino-5-chloro-thiophenol, 2-nitro-5-chloro-thiophenol, 2,4-dimethyl-thiophenol and 2,6-dimethyl-thiophenol.

The selection among the thiophenols of formula II-A depends upon the kind of reaction to be carriedout and, in particular, it depends upon whether the purpose of the reaction is to obtain an unreacted enantiomer III-A with high purity (for example the 2R,3S enantiomer) or to obtain directly a product of formula IV (scheme 1). In the first case the reaction will be carried out between the racemic mixture and any suitable thiophenol II-A while in the second case only 2-amino-thiophenol, 2-nitro-thiophenol, 2-amino-5-chloro -thiophenol or 2 -nitro- 5-chloro-thiophenol will be used.

The amount of thio phenol II-A to be used is from 0.4 to 3 mole per mole of the substrate.

desirable for the higher than 50% second enantiomer compound II-A can as molar amount) Since it is not reaction to proceed with a ccnversion in order to avoid the reaction of the after the first enantiomer) and since be also used in excess (more than 50% with respect to substrate III-A, the course of the reaction must be followed so that the reaction is quenched as soon as the desired conversion is reached. Generally, it is preferred to use from 0.4 to 1 mole of thiophenol II-A per mole of substrate and it is still more preferred to use from 0.5 to 0.7 mole of compound II-A per mole of compound III-A.

Catalyst Examples of optically active tertiary amines useful for the process of the invention are optically active cinchona bases, N,N-dialkyl-ephedrines, dialkylphenylamines, Ot- or a-hydroxy-trialkylamines. Cinchona bases such as cinchonine, dihydrocinchonidine, quinine, quinidine and cinchonidine are preferred. Among the cinchona bases, cinchonidine is the most preferred. Quaternary ammonium salts of the above bases can be used too, optionally in the presence of another base.

When cinchonidine is used together with, forexample, racemic trans III-A, the 2S,3R enantiomer reacts while the desired 2R,3S enantiomer remains substantially unchanged in solution, obviously by quenching the reaction at about 50% conversion. The molar amount of catalyst to be used is between 3 and 50% with respect to compound III-A, preferably between 10 and 50% The tertiary amine can be recovered quantitatively at the end of the reaction.

Solvent It is preferred to dissolve compound II-A in the reaction medium, but it is not necessary that substrate III-A and the tertiary amine are completely dissolved. Then, suitable solvents are those inert under the reaction conditions and able to dissolve compound II-A as well as, at least partially substrate III-A and the tertiary amine. Examples of preferred solvents are benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene and mixtures of two or more thereof.

practically 1 14.

- Temperature The temperature range for the reaction is from -200C +300C. By working below -20'C, the reaction runs too slowly from an industrial point of view even if it provides the desired results. On the contrary, at temperatures above 3CC, the selectivity required in order to carry out the kinetic resolution object of the invention is partially lost. Within the stated temperature range, the desired degree of conversion (50%) is reached in about 4 to 24 hours.

to Practical embodiment of the process of the invention consists in reacting a mixture of compound III-A, compound II-A and the optically active tertiary amine in an inert solvent, for example an aromatic solvent, at the selected temperature. The course of the reaction is followed and, when the desired degree of conversion is reached (about 50% of compound III-A), the reaction is quenched by pouring the reaction mixture into an aqueous acid. The optically active tertiary amine, which is recycled, is recovered from the aqueous layer. From the organic layer, unreacted enantiomer IIIA is separated from reaction product IV-A.

If compound IV-A has the desired configuration, it is further transformed as described in scheme 1 in order to obtain the corresponding compound of formula 1. On the contrary, if the unreacted enantiomer III-A has the right configuration, it is reacted with 2-amino-thiophenol (or 2-nitrothiophenol) according to scheme 1.

The enantiomeric purity of the obtained product or of the unreacted enantiomer is high and, therefore, the usual workup in the subsequent steps of the process for the synthesis of the compounds of formula 1 (for example scheme 1) allows the desired final products to be obtained with an optical purity according to Pharmacopoeia requirements, without further optical separations. Therefore, the process of the invention shows several advantages which are useful from an industrial point of view.

In fact, as far as we know, the process of the invention is the first example of a non-enzymatic ki.netic resolution to separate the enantiomers of formula III-A and it allows the optical separation to be carried out in the first step of the process for the synthesis of the compounds of formula 1. In addition, the practical realization of the process of the invention is simple and does not require any special equipment; the optically active tertiary amine is easily recovered and recycled.

The following Examples illustrate the invention.

Example 1

Cinchonidine (1.5 g; 5 mmol) and, subsequently 2-amino-thiophenol (0.62 g; 5 mmol) were added, under stirring at 200c, to a solution of racemic trans-3-(4-methoxyphenyl)-glycidic acid methyl ester (2 g; 10 mmol) in toluene (20 ml). The reaction mixture was kept under stirring at 20C for 20 hours and poured under stirring into 1N hydrochloric acid solution (20 M1) The phases were separated and the aqueous phase was extracted with dichloromethane (20 ml). The collected organic phases were washed with water (20 ml) and dried on anhydrous sodium sulphate. The evaporation of the solvent under vacuum left a crude compound containing, according to HPLC and 1 H-NMR analysis, (2R,3S)-trans-3-(4-methoxyphenyl-glycidic acid methyl ester (0.95 g). The ester was isolated by chromatography on silica gel using a mixture of n.hexane:

diethyl ether=8:2 by volume as eluent. (2R,3S)-3- 12 (4methoxyphenyl)-glycidic acid methyl ester (0.6 g) with a 60% enantiomeric excess was obtained.

The methyl ester was dissolved in toluene (4.2 ml) and 2-amino-thiophenol (0.36 g; 2.88 mmol) was added to the solution. The mixture was heated under reflux for 2 hours and then cooled to room temperature. The insoluble residue was filtered off and dried under vacuum in an oven (25, 3S)-2-hydroxy-3(2-aminophenylthio) -3-(4-methoxyphenyl)-propionic acid methyl ester with 72% enantiomeric purity ([ (xl D 20 =+720 - c=0.5% CHCl 3) was obtained. The enantiomeric purity by HPLC on chiral column was 80% Example 2

Cinchonidine (3.7 9; 12.6 mmol) and, subsequently, 2-amino-thiophenol (2. 4 g; 19 mmol) were added, under stirring and under nitrogen at T'C, to a solution of racemic trans-3(4-methoxyphenyl)-glycidic acid methyl ester (8 g; 38mmQ1) in toluene (80 ml). The reaction mixture was kept under stirring at CC for 24 hours and poured under stirring into 1N hydrochloric acid solution (80 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (80 ml). The collected organic phases were washed with water (80 ml) and dried on anhydrous sodium sulphate. HPLC analysis (chiral column) of the solution was carried out. The solution contained trans-3-(4-methoxyphenyl)-glycidic acid methyl ester (4.72 g; 22.7 mmol) with a ratio (2R,3S:(2S,3R)=73:27.

Example 3

Cinchonidine (2.82 g; 9.6 mmol) and, subsequently, 2-amino-thiophenol (1. 68 g; 13.44 mmol) were added, under stirring and under nitrogen at OOC, to a solution of racemic trans3-(4methoxyphenyl)-glycidic acid methyl ester (4 g; 19.2 mmol) in toluene (40 ml). The ZI 1 1 1 - 13 reaction mixture was kept under stirring at OC for 24 hours and poured under stirring into 1N hydrochloric acid solution (40 ml). The phases were separated and the aqueous phase was extracted with dichloromethane(40 M1). The collected organic phases were washed with water (40 ml) and dried on anhydrous sodium sulphate. HPLC analysis (chiral column) of the solution was carried out. The solution contained trans-3-(4-methoxyphenyl) -glycidic acid methyl ester (1.6 g; 7.7 mmol) with a ratio (2R,3S):(2S,3R)=85:1S.

Claims (10)

1. A process for the kinetic resolution of a mixture of cis or trans enantiomers of a compound of formula 0 -CH-CH-CO-R3 (III-A) wherein R 3 represents a linear or branched C 1- C 18 alkoxy group, a benzyloxy or amino group, or a mono or dialkylamino group in which the or each alkyl. moiety has from 1 to 6 carbon atoms; X represents a methoxy group or a group transformable into a methoxy group, said transformable group being a free hydroxy group or a hydroxy group protected as benzyloxy or as an ester with an acid usually used for protecting phenols; and the asterisks mark the asymmetric carbon atoms; the process comprising reacting a racemic mixture of cis or trans enantiomers of the compounds of formula III-A with a thiophenol of formula SH R., -CO Res (II-M wherein each of R 4 and R 5 independently represents a hydrogen or chlorine atom, or a C 1C 4 alkyl, amino, acetylamino or nitro group; in the presence of a catalytic amount of an optically active tertiary amine in an inert solvent at a temperature of from -20C to +30C.

2. A process according to claim 1 in which a compound of formula 1 - X 1-0- S R,- 0 OH COR 3 Ris (IV-A) wherein R 3 ' R 4 ' R 5 and X are as defined in claim 1 isolated.

3. A process according to claim 1 or claim 2 - in which the unreacted compound III-A is isolated.

4. A process according to any preceding claim in which, when the molar amount of thiophenol II-A is higher than 50% with respect to compound IIIA, the reaction is quenched at about 50% conversion of compound III-A.

5. A process according to any preceding claim in which the thiophenol of formula II-A isthiophenol, 4-methyl-thiophenol, 4-isopropyl-thiophenol, 4-tert.butyl-thiophenol, 2-amino-thiophenol, 2-nitro -thiophenol, 2-amino-5-chloro-thiophenol, 2-nitro-5 -chloro-thiophenol, 2,4-dimethyl-thiophenol or 2,6-dimethyl-thiophenol.

6. A process according to any preceding '.t laim in which the optically active tertiary amine is an N,N-dialkyl-ephedrine, a dialkylphenylamine, an a - or 0-hydroxy-trialkylamine, cinchonine, dihydrocinchonidine, quinine, quinidine or cinchonidine or a quaternary ammonium salt thereof.

1

7. A process according to claim 5 in which the optically active tertiary amine is cinchonidine.

8. A process according to any preceding claim in which the molar amount of the optically active tertiary amine is between 3 and 50% with respect to compound III-A.

9. A process according to any preceding claim in which the solvent is benzene, toluene, o-xylene, mxylene, p-xylene, chlorobenzene, odichlorobenzene, mdichlorobenzene, p-dichlorobenzene or a mixture of two or more thereof.

10. A process for the kinetic resolution of a mixture of cis or trans enantiomers of a compound of formula III-A as defined in claim 1, the process being substantially as described herein with reference to any of the Examples.

J Published 1991 at The Patent Office. Concept House. Cardiff Road, Newport. Gwent NP9 IlRdi. Further copies may be obtained from Sales Branch, Unit 6. Nine Mile Point Cwnifelinfach. Cross Keys. Newport. NP1 7HZ Printed by Multiplex techniques lid. St Mary Cray, Kent.